The present invention relates to a pharmaceutical matrix film tablet with controlled release of natural mixtures of conjugated estrogens which have been obtained from the urine of pregnant mares.
Estrogens are used in medicine for hormone replacement therapy. In particular, estrogen mixtures are used for the treatment and prophylaxis of the disorders of the climacteric period which occur in women after natural or artificial menopause. In this case, natural mixtures of conjugated estrogens such as are found in the urine of pregnant mares have proved particularly effective and readily compatible.
The dissolved solids content in the urine of pregnant mares (=pregnant mares' urine, abbreviated hereafter as “PMU”) can naturally vary within wide ranges, and may generally lie in a range of 40 to 90 g dry matter per liter. In addition to urea and other usual urine contents, phenolic constituents, e.g. cresols and dihydro-3,4-bis[(3-hydroxyphenyl)methyl]-2(3H)-furanone, known as HPMF, are contained in the solids content of the PMU. The natural mixture of estrogens contained in the PMU is largely present in conjugated form, e.g. as sulfuric acid semi-ester sodium salt (abbreviated hereafter as “sulfate salt”). The content of conjugated estrogens (abbreviated hereafter as “CE”), calculated as estrogen sulfate salt and relative to dry matter, may be between 0.3 and 1% by weight.
Upon separation of the undesirable accompanying substances, such as urea and in particular cresols and HPMF, usually extracts are obtained from the PMU which contain the conjugated estrogens from pregnant mares' urine (PMU) in dissolved form. More recent methods obtain natural mixtures of these conjugated estrogens (CE) by solid-phase extraction of the mixture of conjugated estrogens from pregnant mares' urine e.g. on RP silica gel (U.S. Pat. No. 5,814,624) or on non-ionic semipolar polymeric adsorption resins (U.S. Pat. No. 5,723,454). Although the undesirable accompanying substances can be separated out of the PMU more effectively and more efficiently with these methods and aqueous extracts of the CE of good quality can be obtained, the concentration of the CE in the extract is subject to certain unavoidable fluctuations, since PMU, as a natural starting material for obtaining the CE per se is subject to natural fluctuations in quality due to its origin, storage, transport and any pre-processing.
Due to the properties of the extracts of natural mixtures of conjugated estrogens obtained in this way and in particular also due to the accompanying substances which usually still remain therein after working-up, it is not easy to convert these extracts galenically into solid pharmaceutical preparations of reliable quality. In the production of solid pharmaceutical preparations of natural mixtures of conjugated estrogens from CE-containing extracts, however a constant quality and dose strength of the preparation and a predetermined release profile must be ensured. The natural fluctuations in the content of conjugated estrogens in the extracts used for the production of pharmaceutical preparations which occur dependent on the yield and quality of the PMU starting material therefore have to be compensated for by suitable galenic processing, so that solid pharmaceutical preparations of natural mixtures of conjugated estrogens with constant quality, dose strength and also predetermined release profile can be provided.